The present invention refers to a novel, industrially acceptable processes for the preparation and purification of cis-2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine, from a cis/trans-mixture of isomers. The hydrochloride salt of the cis-isomer of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine is the active ingredient in Cevimeline hydrochloride. This pharmaceutical is useful for the treatment of diseases of the central nervous system due to disturbances of central cholinergic function and autoimmune system (Sjörgen's syndrome) and is marketed as Evoxac®
U.S. Pat. No. 4,855,290 teaches a process for the preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine, wherein the cis-isomer is isolated via fractional recrystallization of its hydrochloric salt. A major disadvantage of this method is the use of repeated (up to 6 times) recrystallizations of the hydrochloride salt of a cis/trans-mixture of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine. This procedure results in an enriched mother liquor in the cis-isomer that by subsequent chromatographic purification, again undesirable in industrial settings, results in the isolation of the cis-isomer in less than 10% yield. Another drawback of the above procedure is the use of the moisture sensitive and highly reactive boron trifluoride etherate. This reagent is not easy to handle and as such, requires special operations to prevent corroding of the reactors. Also, it should be pointed out that U.S. Pat. No. 4,855,290 uses dichloromethane, an environmentally unfriendly solvent.
U.S. Pat. No. 4,981,858 describes a process for the resolution of the enantiomers of the cis and trans diastereomers of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine. For example, a racemic sample of the cis or trans diastereomer of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine is heated with L-tartaric acid in absolute ethanol, followed by fractional recrystallization of the dextrorotatory enantiomer from ethanol. Treatment of the mother liquor with D-tartaric acid allows for isolation of the levorotatory enantiomer. This patent though does not teach any industrially acceptable processes for the preparation and purification of the cis-isomer of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine.
U.S. Pat. Nos. 5,571,918 and 4,861,886 describe the isomerization of trans-2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine to the cis-form in the presence of various acids such as tin tetrachloride. Like boron trifluoride, tin tetrachloride is a very toxic and moisture sensitive chemical, which makes it a hazardous and industrially unfriendly choice, especially when transiting to commercial scale. Also, in terms of delivering pharmaceutical-grade quality Cevimeline hydrochloride (i.e., >99.5% of the cis-isomer), we found that these procedures were either inadequate or too hazardous to be practical.
The lack of industrially advantageous processes for the preparation of the cis-isomer of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine prompted us to search for novel and industrially acceptable processes for the preparation and purification of the cis-isomer.
Further and other objects of the invention will be realized by those skilled in the art from the following Summary of the Invention and Detailed Description of Preferred Embodiments of the Invention thereof.